Internationally, there are 22 million HIV-infected individuals; 8 million people have already died from AIDS. A major focus within our laboratory has been to define the unique epidemiologic, clinical, virologic, and immunologic features of HIV-1 and HIV-2 infections in developing countries and in the U.S.. In Pune, India, we have screened 8,134 patients attending sexually transmitted disease (STD) clinics, of whom 23% are HIV positive. In a prospective study the incidence rate of HIV infection was 16.2% among female sex workers, 7.4% among men and 6.6% among married spouses of these men. The high frequency of multiple STDs and HIV infection coupled with low condom use and low AIDS awareness contribute to the rapid spread of HIV into both high and lower risk populations in India. Genetic analysis of viral strains in newly infected individuals in Pune demonstrated the prevalence of HIV-1 subtype C2 and C3. Immunologic studies of patients with acute primary infection showed that individuals infected with subtype C generate cross-reactive CTL responses that are directed against both subtype C and subtype B. In a multicenter study on perinatal transmission in the U.S., we determined that elevated RNA viral levels at birth were suggestive of in utero infection and that a high plasma RNA viral load in the first two months of life (> 300,000 copies per ml) was strongly associated with rapid progression to AIDS or death. None of the infants with < 70,000 HIV RNA copies/ml progressed to AIDS, suggesting that antiretroviral therapy in infants with high viral loads should result in improved survival and delayed progression. In addition, co-infection of the mother with HIV and hepatitis C virus resulted in a three-fold increase in perinatal transmission of HCV and a two-fold increase in perinatal transmission of HIV. In a study of asymptomatic HIV-infected patients, there appears to be an extremely low total body load of latently infected resting CD4+ T cells with a DNA-integrated virus which is replication competent (< 10/7 cells). The reservoir of these latently infected resting T cells was < 0.05% of the CD4+ T-cell population. Additional studies on HIV viral load demonstrated that at the time of an acute opportunistic infection, HIV RNA may increase three- to five-fold, which subsequently declines to the baseline viral RNA level 3 months following successful treatment. The changes in viral RNA correlated best with changes in cytokines associated with immune activation. In a community-based STD mass treatment campaign of 10,000 individuals in Uganda, there was a 60% reduction in the prevalence and incidence of bacterial STDs. The prevalence of HIV was significantly associated with bacterial vaginosis. Current attempts to control bacterial vaginosis and other STDs could potentially reduce heterosexual transmission of HIV. Additional future studies will address the effect of mass treatment of STDs during pregnancy on perinatal outcomes including the correlation of maternal viral RNA and perinatal transmission.